Epidermal Growth Factor Receptor Translocation to the Mitochondria REGULATION AND EFFECT
Epidermal Growth Factor Receptor Translocation to the Mitochondria REGULATION AND EFFECT
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DOI：
10.1074/jbc.m109.000760
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发表时间：
2009-12-25
影响因子：
4.8
通讯作者：
Parsons, Sarah J.
中科院分区：
文献类型：
--
作者：
Demory, Michelle L.;Boerner, Julie L.;Parsons, Sarah J.
表皮生长因子（EGF）受体（EGFR）和c - Src的共过度表达经常发生在人类肿瘤中，并与肿瘤生长增强相关。在实验系统中，这种协同生长需要c - Src与EGFR的EGF依赖性结合以及c - Src对受体Tyr - 845的磷酸化。对Tyr(P) - 845信号传导介质的研究表明，线粒体细胞色素c氧化酶亚基II（CoxII）以Tyr(P) - 845和EGF依赖的方式与EGFR结合。在细胞中，这种结合涉及EGFR向线粒体的易位，但这一过程的调节机制尚不明确。当前的研究表明，c - Src以与EGFR相似的动力学转移到线粒体，并且EGFR和c - Src的催化活性以及内吞作用和线粒体定位信号是这些事件所必需的。CoxII可被EGFR和c - Src磷酸化，并且EGF刺激会降低Cox活性和细胞ATP，这一事件在很大程度上依赖于定位于线粒体的EGFR。这些发现表明EGFR通过与CoxII的结合和修饰在调节线粒体功能方面发挥着新的作用。
Co-overexpression of the epidermal growth factor (EGF) receptor (EGFR) and c-Src frequently occurs in human tumors and is linked to enhanced tumor growth. In experimental systems this synergistic growth requires EGF-dependent association of c-Src with the EGFR and phosphorylation of Tyr-845 of the receptor by c-Src. A search for signaling mediators of Tyr(P)-845 revealed that mitochondrial cytochrome c oxidase subunit II (CoxII) binds EGFR in a Tyr(P)-845- and EGF-dependent manner. In cells this association involves translocation of EGFR to the mitochondria, but regulation of this process is ill-defined. The current study demonstrates that c-Src translocates to the mitochondria with similar kinetics as EGFR and that the catalytic activity of EGFR and c-Src as well as endocytosis and a mitochondrial localization signal are required for these events. CoxII can be phosphorylated by EGFR and c-Src, and EGF stimulation reduces Cox activity and cellular ATP, an event that is dependent in large part on EGFR localized to the mitochondria. These findings suggest EGFR plays a novel role in modulating mitochondrial function via its association with, and modification of CoxII.